Poly(ADP-ribose)polymerase, hereinafter to be abbreviated as “PARP”, is an intranuclear enzyme that utilizes nicotinamide nucleotide (NAD) as a substrate, cleaves the bond between nicotinamide and ribose, transfers ADP-ribose residue into a protein, and causes addition polymerization of plural ADP-ribose residues. This enzyme is attractive as an apoptosis-related enzyme, which is considered to be activated by recognizing the nick of DNA damaged by a free radical, such as nitrogen monoxide, active oxygen and the like, which is produced in the lesion during ischemia, and have a primary role to aid DNA repair.
It is considered in recent years that the activation of PARP decreases intracellular NAD, a large amount of ATP is consumed to compensate for the decrease, as a result of which intracellular energy is depleted, and the cell is driven to death. In an experiment using a PARP knockout mouse, it has been clarified that a cultured neuronal cells show resistance to disorders due to nitrogen monoxide, excitatory amino acids such as NMDA (N-methyl-D-aspartate) and the like, and that it shows a tremendous protective effect by inhibiting cerebral infarction by not less than 80% in cerebral ischemia model (Eliasson M J L. et al., Nature Med., 3, 1089-95 (1997)).
However, none of the reported PARP inhibitors to date has subjected to a clinical trial as a therapeutic agent for cerebral infarction. As the reported PARP inhibitors to date, for example, 5-substituted-3,4-dihydro-2H-isoquinoline derivatives (EP 355750 A), 1,11b-dihydrobenzopyrano[4.3.2-de]isoquinolin-3-one derivatives (WO99/11645), 3,4-dihydro-5-[4-(1-piperidinyl)-butoxy]-1(2H)-isoquinoline (each of WO99/08680 and WO99/11649), pyrimidine derivatives (WO00/42025), benzimidazole derivatives (each of WO00/64878 and WO00/68206), phthalazine derivatives (each of WO00/67734, WO00/44726 and WO 01/79184), quinazolinone derivatives (each of WO02/48117 and WO02/44157) and the like are known, but the PARP inhibitory activity thereof is not very strong.
Moreover, JP-B-S46-12454 discloses isoquinoline derivatives having an analgesic action and a hypoglycemic action, U.S. Pat. No. 4,113,731 discloses a production method of 3H-pyrazolo[3,4-c]isoquinolin-5(4H)one derivatives, Chemical & Pharmaceutical Bulletin (Chem. Pharm. Bull., Vol. 19 (No. 11), 1971, p. 2414) discloses 2-methyl-4-dimethylaminomethylisoquinolin-1-one, YAKUGAKU ZASSHI (Vol. 91 (No. 12), p. 1279, 1971) discloses 3-amino-4-acetyl-2H-isoquinolin-1-one, JP-B-S52-156875 discloses a production method of 4-dialkylaminomethyl-2H-isoquinolin-1-one derivatives, and JP-B-S54-84597 discloses condensed isoquinolin-1-one derivatives. However, none of these compounds takes note of the PARP inhibitory activity.    [patent reference 1] EP 355750 A    [patent reference 2] WO99/11645    [patent reference 3] WO99/08680    [patent reference 4] WO99/11649    [patent reference 5] WO00/42025    [patent reference 6] WO00/64878    [patent reference 7] WO00/68206    [patent reference 8] WO00/67734    [patent reference 9] WO00/44726    [patent reference 10] WO01/79184    [patent reference 11] WO02/48117    [patent reference 12] WO02/44157    [patent reference 13] JP-B-S46-12454    [patent reference 14] U.S. Pat. No. 4,113,731    [patent reference 15] JP-B-S52-156875    [patent reference 16] JP-B-S54-84597    [non-patent reference 1] Eliasson M J L. et al., Nature Med., 3, 1089-95 (1997)    [non-patent reference 2] Chemical & Pharmaceutical Bulletin (Chem. Pharm. Bull., Vol. 19 (No. 11), 1971, p. 2414)    [non-patent reference 3] YAKUGAKU ZASSHI (Vol. 91 (No. 12), p. 1279, 1971)